The 5-HT(1A) receptor and hallucinogens

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Use of hallucinogens, such as lysergic acid diethylamide (LSD), continues to be a societal problem and accordingly is a major interest of the National Institute on Drug Abuse. Hallucinogens are worthy of study not only because they have significant abuse liability but also because a detailed understanding of their mechanisms of action may be informative with respect to a variety of psychiatric disorders including psychosis. The psychotropic actions of indoleamine (e.g., LSD) and phenethylamine (e.g., mescaline) hallucinogens appear to involve activation of 5-HT 2A receptors. However, this activation is modulated by other serotonergic and non-serotonergic receptors. The objective of the project was to determine the modulatory influence of 5-HT 1A receptors on the stimulus effects of LSD, and to determine the mechanism by which this modulation occurs. It has been suggested that the 5-HT 1A receptor plays a significant modulatory role in the stimulus effects of the hallucinogen lysergic acid diethylamide (LSD). Initial studies sought to characterize the effects of several compounds with known affinity for the 5-HT 1A receptor on the discriminative stimulus effects of LSD. Rats were trained in a two-lever, fixed ratio10, food reinforced task with LSD (0.1 mg/kg; IP; 15 min pretreatment) as a discriminative stimulus. Combination and substitution tests with the 5-HT 1A agonists, 8-hydroxy-2-(di- N -propylamino)tetralin (8-OH-DPAT), buspirone, gepirone, and ipsapirone, with LSD-induced stimulus control were then performed. The effects of these 5-HT 1A ligands were also tested in the presence of the selective 5-HT 1A receptor antagonist, WAY-100,635 (0.3 mg/kg; SC; 30 min. pretreatment). In combination tests stimulus control by LSD was increased by all 5-HT 1A receptor ligands with agonist properties. Similarly, in tests of antagonism, the increase in drugappropriate responding caused by stimulation of the 5-HT 1A receptor was abolished by administration of WAY-100,635. These data support the hypothesis that the 5-HT 1A receptor has a significant modulatory role in the stimulus effects of LSD. Observations from the preceding study resulted in investigations to test the hypothesis that ligands which were active at 5-HT 2A receptors had a modulatory influence on 5-HT 1A receptor function. Initial studies sought to characterize the effects of the selective 5-HT 2A antagonist M100907 on the discriminative stimulus effects of 8-OHDPAT. Rats were trained in a two-lever, fixed ratio10, food reinforced task with the prototypical 5-HT 1A agonist 8-OH-DPAT (0.2 mg/kg; IP; 15 min pretreatment) as a discriminative stimulus. Stimulus control by 8-OH-DPAT was attenuated by the selective 5-HT 2A antagonist M100907 (0.1 mg/kg; 30 min pretreatment time). In addition, 8-OH-DPAT generalized to the 5-HT 1A agonist buspirone (1.0 mg/kg; 15 min pretreatment time) and this substitution was also attenuated by M100907. These data suggest that 5-HT 2A receptors may have a role in the stimulus properties of 8-OH-DPAT and that the interactions between 5-HT 1A and 5-HT 2A receptors are bidirectional in drug discrimination studies. Based on our behavioral studies the mechanisms of action of LSD, and the observed 5-HT 1A -5-HT 2A receptor interactions were investigated. While previous studies have suggested a prominent role for 5-HT 1A and 5-HT 2A receptors in the mechanism of action of LSD, glial cells and other cytological sites of action may contribute to the drug's effects. To this end, c-Fos was employed as a marker of cellular activation to determine the specific cell types which are activated by administration of LSD. Adult male F344 rats were injected with LSD and sacrificed 90 min later. Brains were removed, and the prefrontal cortex was examined for c-Fos expression by immunohistochemistry. Dose-response studies revealed that LSD-induced c-Fos expression is dose related. Double labeled immunohistochemistry revealed that LSD induced c-Fos expression occurs in neurons, and oligodendrocytes. Because c-Fos is an inducible transcription factor, these results suggest that dose related changes in gene expression may result from, and contribute to the behavioral effects of LSD. Our finding that LSD-induced c-Fos expression occurs in oligodendrocytes suggests these cells may be involved in the acute behavioral effects of LSD or stimulated as a consequence of LSD administration.